Intraocular pressure-lowering agent comprising compound having histone deacetylase inhibitor effect as active ingredient

Abstract

An object of the present invention is to find a novel pharmacological effect of a compound having an HDAC inhibitory effect. The compound having an HDAC inhibitory effect of the invention has an excellent effect of cell morphological change on trabecular meshwork cells and/or effect of intraocular pressure reduction, and is therefore useful as a preventive and/or therapeutic agent for a disease considered to be associated with aqueous humor circulation and/or intraocular pressure, particularly as a preventive and/or therapeutic agent for glaucoma or ocular hypertension.

1 . An intraocular pressure-lowering agent comprising at least one compound having a histone deacetylase inhibitory effect as an active ingredient. 
   
   
       2 . The intraocular pressure-lowering agent according to  claim 1 , wherein the compound having a histone deacetylase inhibitory effect is a compound selected from the following compounds or a salt thereof
 (2E,4E,6R)-7-(4-Dimethylaminophenyl)-N-hydroxy-4,6-dimethyl-7-oxo-2,4-heptadienamide (Trichostatin A),   N-Hydroxy-N′-phenyloctanediamide (SAHA),   4-Dimethylamino-N-(6-hydroxycarbamoylhexyl)benzamide (M 344),   (E)-N-Hydroxy-5-[3-(phenylsulfonylamino)phenyl]-2-penten-4-ynamide (Oxamflatin),   N-Hydroxy-3-[3-hydroxyamino-3-oxo-1-propenyl]benzamide (CBHA),   (E)-N-Hydroxy-3-[1-methyl-4-(4-methylbenzoyl)-1H-pyrrol-2-yl]-2-propenamide (MC1293),   (1R)-[(2S,3S)-3-[(E)-2-[(2S,3S)-3-[(1R)-Hydroxyethyl]oxiran-2-yl]vinyl]oxiran-2-yl]-2-propen-1-ol (Depudecin),   N-(2-Aminophenyl)-4-(pyridin-3-ylmethyloxycarbonylaminomethyl)benzamide (MS 275),   cyclo[ L -(2-Amino-8-oxodecanoyl)-(1′-methoxy- L -tryptophyl)- L -isoleucyl- D -pipecolinyl] (Apicidin); and   N-(2-Aminophenyl)-4-[4-(pyridin-3-yl)pyrimidin-2-ylaminomethyl]benzamide (free base of MGCD-0103).   
   
   
       3 . The intraocular pressure-lowering agent according to  claim 1 , wherein the compound having a histone deacetylase inhibitory effect is a compound represented by the following general formula (1) or a salt thereof 
     
       
         
         
             
             
         
       
       [wherein R 1  and R 2  are the same or different and represent a hydrogen atom, a lower alkyl group which may have a substituent, a lower alkenyl group which may have a substituent, a lower alkynyl group which may have a substituent or a group represented by the following general formula (2); 
     
     
       
         
         
             
             
         
       
       R 3  represents a hydroxy group, a lower alkoxy group which may have a substituent, a lower cycloalkyloxy group which may have a substituent, an aryloxy group which may have a substituent, a carboxy group, a lower alkoxycarbonyl group which may have a substituent, —OCONR a R b , —NR c R d  or a group represented by the following general formula (3); 
     
     
       
         
         
             
             
         
       
       R 4  and R 5  are the same or different and represent a halogen atom, a lower alkyl group which may have a substituent, a hydroxy group, or a lower alkoxy group which may have a substituent; 
       R 6  represents a halogen atom, a lower alkyl group which may have a substituent, a lower cycloalkyl group which may have a substituent, an aryl group which may have a substituent, a heterocyclic group which may have a substituent, a hydroxy group, a lower alkoxy group which may have a substituent, a lower cycloalkyloxy group which may have a substituent, an aryloxy group which may have a substituent, a mercapto group, a lower alkylthio group which may have a substituent, a lower cycloalkylthio group which may have a substituent, an arylthio group which may have a substituent, a formyl group, a lower alkylcarbonyl group which may have a substituent, a carboxy group, a lower alkoxycarbonyl group which may have a substituent, a nitro group, a cyano group or —NR e R f ; 
       R 7  represents a lower alkyl group which may have a substituent, a lower cycloalkyl group which may have a substituent, an aryl group which may have a substituent, a hydroxy group, a lower alkoxy group which may have a substituent, a lower cycloalkyloxy group which may have a substituent or an aryloxy group which may have a substituent; 
       R a  and R b  are the same or different and represent a hydrogen atom, a lower alkyl group which may have a substituent, a lower cycloalkyl group which may have a substituent, an aryl group which may have a substituent or a heterocyclic group which may have a substituent; 
       R c , R d , R e  and R f  are the same or different and represent a hydrogen atom, a lower alkyl group which may have a substituent, a lower cycloalkyl group which may have a substituent or an aryl group which may have a substituent; 
       the ring A represents a cyclic hydrocarbon or a heterocyclic ring; 
       the ring B represents a heterocyclic ring having one or plural heteroatoms selected from the group consisting of a nitrogen atom and an oxygen atom in the ring; 
       X represents a lower alkylene group which may have a substituent; 
       Y and Z are the same or different and represent a single bond or a lower alkylene group which may have a substituent; 
       W 1 -W 2  represents N—C or C—N; and 
       l, m, n and o are the same or different and represent 0, 1, 2 or 3]. 
     
   
   
       4 . The intraocular pressure-lowering agent according to  claim 3 , wherein in the general formula (1),
 R 1  and R 2  are the same or different and represent a hydrogen atom, a lower alkyl group, a lower alkyl group having a halogen atom as a substituent, a lower alkyl group having a methoxy group as a substituent, a lower alkyl group having a methylthio group as a substituent, a lower alkyl group having a cyano group as a substituent, a lower alkyl group having a methylaminocarbonyl group as a substituent, a lower alkyl group having a diisopropylamino group as a substituent, a lower alkenyl group, a lower alkynyl group or a group represented by the following general formula (2);   
     
       
         
         
             
             
         
       
       R 3  represents a hydroxy group, a lower alkoxy group, a lower cycloalkyloxy group, an aryloxy group, a carboxy group, a lower alkoxycarbonyl group, —OCONR a R b , —NR c R d  or a group represented by the following general formula (3); 
     
     
       
         
         
             
             
         
       
       R 4  and R 5  are the same or different and represent a halogen atom, a lower alkyl group, a hydroxy group or a lower alkoxy group; 
       R 6  represents a halogen atom, a lower alkyl group, a lower alkyl group having a halogen atom as a substituent, a lower alkyl group having a cyano group as a substituent, a lower cycloalkyl group, an aryl group, a heterocyclic group, a hydroxy group, a lower alkoxy group, a lower alkoxy group having a halogen atom as a substituent, a lower alkoxy group having an aryl group as a substituent, a lower cycloalkyloxy group, an aryloxy group, a mercapto group, a lower alkylthio group, a lower cycloalkylthio group, an arylthio group, a formyl group, a lower alkylcarbonyl group, a carboxy group, a lower alkoxycarbonyl group, a nitro group, a cyano group or —NR e R f ; 
       R 7  represents a lower alkyl group, a lower cycloalkyl group, an aryl group, a hydroxy group, a lower alkoxy group, a lower cycloalkyloxy group or an aryloxy group; 
       R a  and R b  are the same or different and represent a hydrogen atom, a lower alkyl group, a lower cycloalkyl group, an aryl group or a heterocyclic group; 
       R c , R d , R e  and R f  are the same or different and represent a hydrogen atom, a lower alkyl group, a lower cycloalkyl group or an aryl group; 
       the ring A represents a cyclic hydrocarbon or a heterocyclic ring; 
       the ring B represents a heterocyclic ring having one or plural heteroatoms selected from the group consisting of a nitrogen atom and an oxygen atom in the ring; 
       X represents a lower alkylene group; 
       Y and Z are the same or different and represent a single bond, a lower alkylene group or a lower alkylene group having an oxo group as a substituent; 
       W 1 -W 2  represents N—C or C—N; and 
       l, m, n and o are the same or different and represent 0, 1, 2 or 3. 
     
   
   
       5 . The intraocular pressure-lowering agent according to  claim 3 , wherein in the general formula (1),
 R 1  represents a lower alkyl group, a lower alkyl group having a halogen atom as a substituent, a lower alkyl group having a methoxy group as a substituent, a lower alkyl group having a methylthio group as a substituent, a lower alkyl group having a cyano group as a substituent, a lower alkyl group having a methylaminocarbonyl group as a substituent, a lower alkyl group having a diisopropylamino group as a substituent, a lower alkynyl group or a group represented by the following general formula (2);   
     
       
         
         
             
             
         
       
       R 2  represents a hydrogen atom; 
       R 3  represents a hydroxy group, a carboxy group, a lower alkoxycarbonyl group, —OCONR a R b , —NR c R d  or a group represented by the following general formula (3); 
     
     
       
         
         
             
             
         
       
       R 6  represents a halogen atom, a lower alkyl group, a lower alkyl group having a halogen atom as a substituent, a lower alkyl group having a cyano group as a substituent, an aryl group, a morpholino group, a hydroxy group, a lower alkoxy group, a lower alkoxy group having a halogen atom as a substituent, a lower alkoxy group having an aryl group as a substituent, a lower alkylthio group, a lower alkylcarbonyl group, a nitro group, a cyano group or —NR e R f ; 
       R 7  represents a lower alkyl group or an alkoxy group; 
       R a  and R b  are the same or different and represent a hydrogen atom, an aryl group or a heterocyclic group; 
       R c , R d , R e  and R f  represent a lower alkyl group; 
       the ring A represents a cyclic hydrocarbon or a heterocyclic ring; 
       the ring B represents a heterocyclic ring having plural heteroatoms selected from the group consisting of a nitrogen atom and an oxygen atom in the ring; 
       X and Y represent a lower alkylene group; 
       Z represents a single bond, a lower alkylene group or a lower alkylene group substituted with an oxo group; 
       W 1 -W 2  represents C—N or N—C; 
       l and m represent 0; 
       o represents 0 or 1; and 
       n represents 0, 1 or 2. 
     
   
   
       6 . The intraocular pressure-lowering agent according to  claim 3 , wherein in the general formula (1), the ring A represents benzene, indan, thiophene, benzo[1,3]dioxole, 2,3-dihydrobenzofuran, 1H-benzimidazole, isoxazole, thiazole, benzothiazole, 2,3-dihydrobenzo[1,4]dioxin or pyridine. 
   
   
       7 . The intraocular pressure-lowering agent according to any one of  claim 3 , wherein in the general formula (1), the ring B represents pyrrolidine or morpholine. 
   
   
       8 . The intraocular pressure-lowering agent according to  claim 1 , wherein the compound having a histone deacetylase inhibitory effect is a compound selected from the following compounds or a salt thereof:
 N-(2-Aminophenyl)-5-[3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-1-(3-dimethylaminopropyl)ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[3-(4-dimethylaminophenyl)-1-(3-(morpholin-4-yl) propyl)ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[1-(3-(morpholin-4-yl)propyl)-3-phenethylureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[3-(3,4-difluorophenyl)-1-(3-dimethylaminopropyl) ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[1-(3-dimethylaminopropyl)-3-(4-methoxyphenyl) ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[3-(4-diethylaminophenyl)-1-(3-dimethylaminopropyl)ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[1-(3-dimethylaminopropyl)-3-(3-fluorophenyl) ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[1-(3-dimethylaminopropyl)-3-(3-fluoro-4-methylphenyl)ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[1-(3-dimethylaminopropyl)-3-(4-fluoro-3-methylphenyl)ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[3-(4-cyanophenyl)-1-(3-dimethylaminopropyl) ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[1-(3-dimethylaminopropyl)-3-(4-trifluoromethoxyphenyl) ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[3-(benzo[1,3]dioxol-5-yl)-1-(3-hydroxypropyl)ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[3-(4-dimethylaminophenyl)-1-(2-ethoxycarbonylethyl)ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[3-(1,3-benzothiazol-2-yl)-1-(3-dimethylaminopropyl)ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[3-(1H-benzimidazol-2-yl)-1-(3-dimethylaminopropyl)ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[3-(2,3-dihydro-1-benzofuran-5-yl)-1-(3-(morpholin-4-yl)propyl)ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-1-(2-hydroxyethyl)ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[1-(3-dimethylaminopropyl)-3-(phenylcarbonylmethyl)ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[1-(3-dimethylaminopropyl)-3-(1,3-thiazol-2-yl)ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[1-(3-dimethylaminopropyl)-3-(6-methoxy-1,3-benzothiazol-2-yl)ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[1-(3-dimethylaminopropyl)-3-(6-fluoro-1,3-benzothiazol-2-yl)ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[1-(3-diethylaminopropyl)-3-(3,4-difluorophenyl)ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[1-(3-(morpholin-4-yl)propyl)-3-(pyridin-3-yl)ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[1-(3-dimethylaminopropyl)-3-(thiophen-3-yl)ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[1-(3-dimethylaminopropyl)-3-(3-fluoro-4-methoxyphenyl)ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[3-(3-chloro-4-fluorophenyl)-1-(3-diethylaminopropyl)ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[1-(3-diethylaminopropyl)-3-(4-fluoro-3-nitrophenyl)ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-1-(2-dimethylaminoethyl)ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[1-(2-dimethylaminoethyl)-3-(3-methoxyphenyl)ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[1-(2-dimethylaminoethyl)-3-(3-fluorophenyl) ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[1-(2-dimethylaminoethyl)-3-(thiophen-3-yl) ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[3-(pyridin-3-yl)-1-[3-(pyrrolidin-1-yl)propyl]ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[1-(3-(morpholin-4-yl)propyl)-3-(phenylcarbonylmethyl)ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[3-(3-chlorophenyl)-1-(3-(morpholin-4-yl)propyl)ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[3-(4-fluorophenethyl-1-(3-(morpholin-4-yl) propyl)ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[3-(4-cyanophenyl)-1-(3-hydroxypropyl)ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[3-(3-fluorophenyl)-1-[2-(4-methylpiperazin-1-yl)ethyl]ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-1-[3-(4-methylpiperazin-1-yl)propyl]ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[1-(2-dimethylaminoethyl)-3-(3-methylphenyl)ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-1-[4-(morpholin-4-yl)butyl]ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[1-(2-dimethylaminoethyl)-3-(1,3-thiazol-2-yl)ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[3-(2-methoxyphenyl)-1-[4-(morpholin-4-yl)butyl]ureidomethyl]pyridine-2-carboxylic acid amide,   N-(2-Aminophenyl)-5-[3-(3-methylphenyl)-1-[3-(4-methylpiperidin-1-yl)propyl]ureidomethyl]pyridine-2-carboxylic acid amide; and   N-(2-Aminophenyl)-5-[3-cyclopentyl-1-[5-(morpholin-4-yl)pentyl]ureidomethyl]pyridine-2-carboxylic acid amide.   
   
   
       9 . A method for changing morphology of trabecular meshwork cells and/or a method for reducing intraocular pressure, comprising administering to a patient an effective amount of the intraocular pressure-lowering agent according to any one of  claims 1  to  8 . 
   
   
       10 . A method for preventing and/or treating a disease associated with aqueous humor circulation and/or intraocular pressure, comprising administering to a patient an effective amount of the intraocular pressure-lowering agent according to any one of  claims 1  to  8 . 
   
   
       11 . A method for preventing and/or treating glaucoma and/or ocular hypertension, comprising administering to a patient an effective amount of the intraocular pressure-lowering agent according to any one of  claims 1  to  8 .